Shields et al. (2003) published a case report on acute myeloid leukemia that presented as bilateral orbital myeloid sarcoma (or chloroma) in a previously healthy 25-month-old boy. Bone marrow biopsy revealed blasts and cells with maturing monocytic features. ... Shields et al. (2003) published a case report on acute myeloid leukemia that presented as bilateral orbital myeloid sarcoma (or chloroma) in a previously healthy 25-month-old boy. Bone marrow biopsy revealed blasts and cells with maturing monocytic features. A final diagnosis of M5b AML was made. The authors reviewed the literature and concluded that leukemia may be the most likely diagnosis in a child with bilateral soft tissue orbital tumors.
Schlenk et al. (2008) studied 872 patients younger than 60 years of age with cytogenetically normal AML and compared mutation status of the NPM1 (164040), FLT3 (136351), CEBPA (116897), MLL (159555), and NRAS (164790) genes in leukemia cells ... Schlenk et al. (2008) studied 872 patients younger than 60 years of age with cytogenetically normal AML and compared mutation status of the NPM1 (164040), FLT3 (136351), CEBPA (116897), MLL (159555), and NRAS (164790) genes in leukemia cells with clinical outcome. There was an overall complete remission rate of 77%. The genotype of mutant NPM1 without FLT3 internal tandem duplications (FLT3-ITD), the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. The authors also found that the benefit of postremission hematopoietic stem cell transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wildtype NPM1 and CEBPA without FLT3-ITD. Gale et al. (2008) found that 354 (26%) of 1,425 patients with AML had the FLT3 internal duplication. The median total mutant level for all patients was 35% of total FLT3, but there was wide variation with levels ranging from 1 to 96%. There was a significant correlation between worse overall survival, relapse risk, and increased white blood cell count with increased mutant level, but the size of the duplication and the number of mutations had no significant impact on outcome. Those patients with the FLT3 duplication had a worse risk of relapse than patients without the FLT3 duplication. Among a subset of 1,217 patients, 503 (41%) had a mutation in the NPM1 gene (164040), and 208 (17%) had mutations in both genes. The presence of an NPM1 mutation had a beneficial effect on the remission rate, most likely due to a lower rate of resistant disease, both in patients with and without FLT3 duplications. Gale et al. (2008) identified 3 prognostic groups among AML patients: good in those with only a NPM1 mutation; intermediate in those with either no FLT3 or NPM1 mutations or mutations in both genes; and poor in those with only FLT3 mutations. Boissel et al. (2011) reviewed the work of several others and performed their own analysis of 205 patients with cytogenetically normal AML, and found that patients with IDH2(R172) mutations had a worse prognosis from those with IDH2(R140) mutations (e.g., 147650.0001). That patients with IDH2(R172) mutations had an unfavorable prognosis by comparison had been noted by Marcucci et al. (2010). The frequency of IDH2(R172) mutations was lower than that of IDH2(R140) mutations among cytogenetically normal AML patients. Boissel et al. (2011) cautioned that patients should be separated by mutation status for prognostic analysis. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukemia patients and are associated with a poor prognosis. Abundant laboratory and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggested that FLT3-ITD probably represents a passenger lesion. Smith et al. (2012) reported point mutations at 3 residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT (164920), PDGFRA (173490), PDGFRB (173410), and RET (164761); evolution of AC220-resistant substitutions at 2 of these amino acids was observed in 8 of 8 FLT3-ITD-positive AML patients with acquired resistance to AC220. Smith et al. (2012) concluded that their findings demonstrated that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML.
In affected members of a family with acute myeloid leukemia, Smith et al. (2004) identified a germline 1-bp deletion (212delC; 116897.0007) in the CEBPA gene. Overt leukemia developed in the father at ... - Mutations in CEBPA In affected members of a family with acute myeloid leukemia, Smith et al. (2004) identified a germline 1-bp deletion (212delC; 116897.0007) in the CEBPA gene. Overt leukemia developed in the father at age 10 years, in the first-born son at age 30 years, and in the last-born daughter at age 18 years. - Mutations in NPM1 NPM, a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF (103180)/p53 (191170) tumor suppressor pathway. Chromosomal translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein. Falini et al. (2005) used immunohistochemical methods to study the subcellular localization of NPM in bone marrow biopsy specimens from 591 patients with primary AML. They then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease. Cytoplasmic NPM was detected in 35.2% of the 591 specimens from patients with primary AML but not in 135 secondary AML (sAML) specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of internal tandem duplications of FLT3 (136351) and absence of CD34 (142230) and CD133 (604365) in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations in the NPM gene (see 164040.0001-164040.0004); this mutant gene caused cytoplasmic localization of NPM in transfected cells. All 6 NPM mutant proteins showed mutations in at least 1 of the tryptophan residues at positions 288 and 290 and shared the same last 5 amino acid residues (VSLRK). Thus, despite genetic heterogeneity, all NPM gene mutations resulted in a distinct sequence in the NPM protein C terminus. Falini et al. (2005) concluded that cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy. Grisendi and Pandolfi (2005) noted that NPM staining in cases of AML with aberrant cytoplasmic localization of the protein is mostly cytoplasmic, which suggests that the mutant NPM acts dominantly on the product of the remaining wildtype allele, causing its retention in the cytoplasm by heterodimerization. By microRNA (miRNA) expression profiling, Garzon et al. (2008) identified 36 upregulated and 21 downregulated miRNAs in AML patients with NPM1 mutations compared with AML patients without NPM1 mutations. miR10A (MIRN10A; 610173) and miR10B (MIRN10B; 611576) showed the greatest upregulation, with increases of 20- and 16.67-fold, respectively. Mir22 (MIRN22; 612077) showed greatest downregulation, with a reduction of 0.31-fold. Garzon et al. (2008) concluded that AML with NPM1 mutations has a distinctive miRNA signature. - Mutations in GATA2 Hahn et al. (2011) analyzed 50 candidate genes in 5 families with a predisposition to myelodysplastic syndrome (614286) and acute myeloid leukemia, and in 3 of the families they identified a heritable heterozygous missense mutation in the GATA2 gene (T354M; 137295.0002) that segregated with disease and was not found in 695 nonleukemic ethnically matched controls. - Mutations in TERT Calado et al. (2009) found a significantly increased number of germline mutations in the TERT gene in patients with sporadic acute myeloid leukemia compared to controls. One mutation in particular, A1062T (187270.0022), was 3-fold higher among 594 AML patients compared to 1,110 controls (p = 0.0009). In vitro studies showed that the mutations caused haploinsufficiency of telomerase activity. An abnormal karyotype was found in 18 of 21 patients with TERT mutations who were tested. Calado et al. (2009) suggested that telomere attrition may promote genomic instability and DNA damage, which may contribute to the development of leukemia. - Somatic Mutations In the bone marrow of a 4-year-old child with AML, Bollag et al. (1996) identified an insertion in the KRAS2 gene (190070.0008). Expression studies showed that the mutant KRAS2 protein caused cellular transformation and activated the RAS-mitogen-activated protein kinase signaling pathway. Bone marrow minimal residual disease causes relapse after chemotherapy in patients with acute myelogenous leukemia. Matsunaga et al. (2003) postulated that the drug resistance is induced by the attachment of very late antigen-4 (VLA4; see 192975) on leukemic cells to fibronectin (135600) on bone marrow stromal cells. Matsunaga et al. (2003) found that VLA4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (see 601232)/AKT (164730)/Bcl2 (151430) signaling pathway, which is activated by the interaction of VLA4 and fibronectin. This resistance was negated by VLA4-specific antibodies. In a mouse model of minimal residual disease, Matsunaga et al. (2003) achieved a 100% survival rate by combining VLA4-specific antibodies and cytosine arabinoside, whereas cytosine arabinoside alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA4-negative patients and 44.4% for 15 VLA4-positive patients. Thus, Matsunaga et al. (2003) concluded that the interaction between VLA4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow minimal residual disease and AML prognosis. Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005) analyzed 300 patients newly diagnosed with AML for mutations in the coding region of the ETV6 gene and identified 5 somatic heterozygous mutations (e.g., 600618.0001 and 600618.0002). These ETV6 mutant proteins were unable to repress transcription and showed dominant-negative effects. The authors also examined ETV6 protein expression in 77 patients with AML and found that 24 (31%) lacked the wildtype 57- and 50-kD proteins; there was no correlation between ETV6 mRNA transcript levels and the loss of ETV6 protein, suggesting posttranscriptional regulation of ETV6. Lee et al. (2006) identified heterozygosity for mutations in the JAK2 gene (147796.0001 and 147796.0002) in bone marrow aspirates from 3 (2.7%) of 113 unrelated patients with AML. Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow cells from 320 patients with myeloid cancers and identified TET2 defects in 2 patients with primary AML and 5 patients with secondary AML. Mardis et al. (2009) used massively parallel DNA sequencing to obtain a very high level of coverage of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome. Mardis et al. (2009) identified 12 somatic mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS (164790) and NPM1 (164040) had been previously identified in patients with AML, but 2 other mutations had not been identified. One of these mutations, in the IDH1 (147700) gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; it is at position 108,115,590 of chromosome 10. The AML genome that was sequenced contained approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis. Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene (612990) may act as a tumor suppressor in myeloid malignancies. They identified heterozygous somatic mutations in the ASXL1 gene in 5 (16%) of 38 myelodysplastic syndrome/acute myeloid leukemia samples. Somatic ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic leukemia (CMML; see 607785) samples. All the mutations were in exon 12 and resulted in truncation of the C-terminal PHD finger of the protein. The findings suggested that regulators of gene expression via DNA methylation, histone modification, and chromatin remodeling could be altered in myelodysplastic syndromes and some leukemias. The same group (Carbuccia et al., 2009) identified heterozygous somatic truncating ASXL1 mutations in 5 (7.8%) of 64 myeloproliferative neoplasms, including 1 essential thrombocythemia (187950), 3 primary myelofibrosis (254450), and 1 AML. Harutyunyan et al. (2011) analyzed biopsy specimens of myeloproliferative neoplastic tissue from 330 patients for chromosomal aberrations associated with leukemic transformation. Three hundred and eight of the patients had chronic-phase myeloproliferative neoplasms and 22 had postmyeloproliferative-phase neoplasm secondary acute myeloid leukemia. Among those 22 patients, 1 carried the MPL W515L mutation and all others carried the JAK2 V617F mutation. Six of the 22 patients carried somatic mutations of TP53 (191170). Three of the patients had independent mutations on both TP53 alleles, and 2 had homozygous mutations because of an acquired uniparental disomy of chromosome 17p. None of the patients with TP53 mutations had amplification of chromosome 1q involving the MDM4 gene (604704). Harutyunyan et al. (2011) concluded that TP53 mutations are strongly associated with transformation to AML in patients with myeloproliferative neoplasms (p = 0.003). Harutyunyan et al. (2011) also found amplification of a region of chromosome 1q harboring the MDM4 gene in 18.18% of patients with secondary AML (p less than 0.001). Ding et al. (2012) determined the mutational spectrum associated with relapse of AML by sequencing the primary tumor and relapse genomes from 8 AML patients, and validated hundreds of somatic mutations using deep sequencing. This method allowed them to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (e.g., WAC; SMC3, 606062; DIS3, 607533; DDX41, 608170; and DAXX, 603186) in AML, Ding et al. (2012) identified 2 major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumor gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations, and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumor mutations in all 8 cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. Ding et al. (2012) concluded that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions. The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. A total of 23 genes were significantly mutated, and another 237 were mutated in 2 or more samples. Nearly all samples had at least 1 nonsynonymous mutation in 1 of 9 categories of genes that were deemed relevant for pathogenesis. The authors identified recurrent mutations in the NPM1 gene in 54/200 (27%) samples, in the FLT3 gene (136351) in 56/200 (28%) samples, in the DNMT3A gene (602769) in 51/200 (26%) samples, and in the IDH1 or IDH2 (147650) genes in 39/200 (20%) samples. Brewin et al. (2013) noted that the study of the Cancer Genome Atlas Research Network (2013) did not reveal which mutations occurred in the founding clone, as would be expected for an initiator of disease, and which occurred in minor clones, which subsequently drive disease. Miller et al. (2013) responded that genes mutated almost exclusively in founding clones in their study included RUNX1 (151385) (9 of 9 mutations in founding clones), NPM1 (164040) (3 of 3 clones), U2AF1 (191317) (5 of 5 clones), DNMT3A (38 of 40 clones), IDH2 (13 of 14), IDH1 (147700) (15 of 17 clones), and KIT (164920) (5 of 6). In contrast, mutations in NRAS, TET2 (612839), CEBPA, WT1 (607102), PTPN11 (176876), and FLT3 were often found in subclones, suggesting that they were often cooperating mutations.
A provisional diagnostic category of “AML with mutated CEBPA” has been set forth in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues [Arber et al 2008, Owen et al 2008, Renneville et al 2008]. Although the WHO category is primarily intended to classify AML with acquired (somatic) mutations in CEBPA, this category also includes inherited (germline) mutations in CEBPA, which are considerably rarer. Note: Most persons with familial or acquired AML with mutated CEBPA have “normal karyotype AML” (i.e., AML in which cytogenetic studies of leukemia cells are normal)....
DiagnosisClinical Diagnosis A provisional diagnostic category of “AML with mutated CEBPA” has been set forth in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues [Arber et al 2008, Owen et al 2008, Renneville et al 2008]. Although the WHO category is primarily intended to classify AML with acquired (somatic) mutations in CEBPA, this category also includes inherited (germline) mutations in CEBPA, which are considerably rarer. Note: Most persons with familial or acquired AML with mutated CEBPA have “normal karyotype AML” (i.e., AML in which cytogenetic studies of leukemia cells are normal).For this GeneReview, the following definitions are used:Familial acute myeloid leukemia (AML) with mutated CEBPA is defined as AML in which a germline CEBPA mutation is present in an affected individual in a pedigree with familial AML. The diagnosis of familial AML with mutated CEBPA is established by either of the following:Detection of a germline CEBPA mutation in a specimen that contains only non-leukemic cells from an individual with AMLDetection of a germline CEBPA mutation in a member of a pedigree in which more than one family member has been affected with AML or myelodysplastic syndrome (MDS) Note: Most individuals with a germline CEBPA mutation appear to have a positive family history of AML.Sporadic AML with mutated CEBPA is defined as AML in which a CEBPA mutation(s) is identified in somatic (i.e., leukemic) cells but a CEBPA mutation is not present in germline (i.e., non-leukemic) cells. Molecular Genetic TestingGene. CEBPA is the only gene known to be associated with familial AML with mutated CEBPA. CEBPA mutations are found in the leukemic cells of approximately 9% of persons with AML, including 15%-18% of persons with normal-karyotype AML [Arber et al 2008, Renneville et al 2008]. However, few of these individuals have a germline CEBPA mutation. Clinical testingSequence analysis. CEBPA has a single exon. Testing involves sequence analysis of the exon. Testing for a germline CEBPA mutation is performed in select individuals with AML (see Testing Strategy) by PCR amplification and direct sequencing of CEBPA in a non-leukemic specimen. Only seven pedigrees with familial AML with mutated CEBPA have been reported. The germline CEBPA mutation was identified in the proband of each pedigree by sequence analysis of non-leukemic cells (Table 2). In all seven pedigrees, the germline mutation was a small deletion, duplication, or insertion resulting in a frameshift causing premature truncation at the N-terminal region of the CEBPA protein (see Molecular Genetics). Note: (1) Testing for a germline mutation should not be performed on blood or bone marrow during active AML. Testing a non-involved specimen, such as cells obtained by buccal swab, is imperative. (2) During clinical remission of AML when the percentage of leukemic cells in blood and bone marrow is very low, a CEBPA mutation that is present only in leukemic cells becomes undetectable. Because the lower limit of detection of a mutant allele by direct sequence analysis is approximately 20% allele proportion, relatively small numbers of morphologically undetectable leukemic cells are not expected to produce false positive results for a germline mutation. Therefore, during remission, testing for germline mutations may be performed with caution on a blood sample, although a buccal swab is preferred. Table 1. Summary of Molecular Genetic Testing Used to Detect Germline Mutations in Familial Acute AML with Mutated CEBPAView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCEBPASequence analysis of non-leukemic cellsGermline sequence variants in the coding region 2>99% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice-site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. The analytic sensitivity of sequence analysis is expected to be >99% for mutations within the coding region. Sequencing of the coding region does not detect putative partial or complete gene deletions or mutations in promoter regions. However, no such germline mutations causing familial AML with mutated CEBPA have been reported to date. Interpretation of test results. Because all seven pedigrees reported with familial AML with mutated CEBPA had a germline mutation that disrupted or predicted a disruption of the N-terminal region of the CEBPA protein, germline variants with similar functional consequences appear to be most common in pedigrees with familial AML with mutated CEBPA.For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis of familial AML with mutated CEBPA in a proband. Testing for germline CEPBA mutations is recommended in:Persons with AML with mutated CEBPA in leukemic cells who have a family history of AML or who have developed AML at an early age;Persons with AML who have a family history of AML, but who have not had CEBPA testing on their leukemic cells.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the germline mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with germline mutations in CEBPA.
Germline CEBPA mutations were only recently discovered as the cause of familial acute myeloid leukemia (AML) with mutated CEBPA and only a limited number of cases have been reported to date; therefore, the true range of clinical phenotypes of this disorder is unknown [Pabst & Mueller 2009]. At this point inherited CEBPA mutations have only been associated with pure familial (i.e., nonsyndromic) AML, which is AML that is not part of broader genetic syndrome such as Fanconi anemia, Bloom syndrome, or Down syndrome. However, this understanding of familial AML with mutated CEBPA could change in the future as more pedigrees are identified. ...
Natural History Germline CEBPA mutations were only recently discovered as the cause of familial acute myeloid leukemia (AML) with mutated CEBPA and only a limited number of cases have been reported to date; therefore, the true range of clinical phenotypes of this disorder is unknown [Pabst & Mueller 2009]. At this point inherited CEBPA mutations have only been associated with pure familial (i.e., nonsyndromic) AML, which is AML that is not part of broader genetic syndrome such as Fanconi anemia, Bloom syndrome, or Down syndrome. However, this understanding of familial AML with mutated CEBPA could change in the future as more pedigrees are identified. The age of onset of familial AML with mutated CEBPA is highly variable, but appears to be earlier than sporadic AML. Disease onset has been reported in persons as young as age four years and older than age 50 years [Pabst et al 2008, Renneville et al 2009]. By contrast, the median age at diagnosis of persons with sporadic AML is 65 years. From an analysis of the seven reported pedigrees with familial AML with mutated CEBPA, it appears that the disease behaves similarly to sporadic AML with mutated CEBPA. Too few patients with familial AML with mutated CEBPA have been reported to know the natural history of the disease; however, the prognosis of individuals with familial AML with mutated CEBPA appears to be favorable (~50%-65% overall survival, compared to the ~25%-40% overall survival of those who have normal karyotype AML but no germline CEPBA mutation). These data are predominantly from persons age 60 years and younger who received standard therapies [Preudhomme et al 2002, Frohling et al 2004, Bienz et al 2005, Marcucci et al 2008]. The positive prognosis associated with AML with mutated CEBPA (familial or sporadic) may be confined to persons with biallelic CEBPA mutations [Pabst et al 2009, Wouters et al 2009, Dufour et al 2010, Green et al 2010]. Individuals with familial AML with mutated CEBPA who have been cured of their initial disease may be at greater risk of developing additional malignant clones than persons who do not have germline CEBPA mutations (i.e., those with sporadic disease) [Pabst et al 2008]. This conjecture is based on the observation that individuals who relapse have somatic CEBPA mutations that differ from those observed in the original leukemia. This phenomenon has not been reported in individuals with sporadic AML with mutated CEBPA who relapse. Pathologic features of leukemic cells in AML with mutated CEBPA (familial or sporadic) include: Normal karyotype A preponderance of French-American-British (FAB) Cooperative Group AML Classification subtypes M1 or M2 as established by review of cellular morphology and cytochemistries in blasts in peripheral blood or bone marrow aspirateMany Auer rods seen in blasts in peripheral blood smear or bone marrow aspirate (Auer rods are abnormal, needle-shaped or round, light blue or pink-staining inclusions found in the cytoplasm of leukemic cells.)Aberrant CD7 expression on blasts in peripheral blood or bone marrow as demonstrated by flow cytometry
The differential diagnosis for familial acute myeloid leukemia (AML) with mutated CEBPA includes:...
Differential DiagnosisThe differential diagnosis for familial acute myeloid leukemia (AML) with mutated CEBPA includes:Sporadic AML with CEBPA mutationsAML secondary to environmental exposures (e.g., benzene, radiation, chemotherapy) *Sporadic AML with more than one affected family member *Note: The more affected individuals in a family (and the closer the relationships) the greater the likelihood of a common cause. RUNX1-mediated familial AMLFamilial AML in association with monosomy 7 (see Familial Mosaic Monosomy 7 Syndrome)Familial AML caused by as-yet undiscovered genes * AML is a relatively rare disease (~13,300 cases/year in the US); therefore, pedigrees with more than one case of AML could have a heritable predisposition or a common exposure [Owen et al 2008].
General evaluation of individuals presenting with signs and symptoms of acute myeloid leukemia (AML) commonly includes: ...
ManagementEvaluations Following Initial Diagnosis General evaluation of individuals presenting with signs and symptoms of acute myeloid leukemia (AML) commonly includes: History and physical examination Complete blood count (CBC) with differential and review of peripheral blood smearPlatelet count Chemistry profile Pathologic bone marrow evaluation Flow cytometryCytochemistries Cytogenetic studies in leukemic cellsIn those with normal-karyotype AML, testing of leukemic cells for mutations in:FLT3 (encoding fms-related tyrosine kinase 3) NPM1 (encoding nucleophosmin) CEBPA To establish the extent of disease and needs of an individual newly diagnosed with AML, the following evaluations are recommended:Cardiac scan in patients with a personal history of – or signs and symptoms suspicious for – heart disease and in those who have received previous anthracycline therapyHLA typing in anticipation of hematopoietic stem cell transplantation (HSCT) Lumbar puncture (LP) if symptoms suggest central nervous system disease. The timing of LP in AML is controversial.Treatment of ManifestationsManagement of familial AML with mutated CEBPA does not differ from that of sporadic AML with mutated CEBPA [National Comprehensive Cancer Network 2009, Döhner et al 2010].Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy with or without hematopoietic stem cell transplantation (HSCT) according to clinical, cytogenetic, and molecular risk. Specific treatment strategies are based on characteristics of the individual patient, response to chemotherapy, treatment setting, and protocol (if the patient is enrolled in a clinical trial). Note: Whenever possible, persons with AML should be treated as part of a clinical trial protocol.Relapses are treated with cytabine-based salvage chemotherapy followed by allogeneic HSCT if a donor is available and if cure is the intent of treatment. Prevention of Secondary ComplicationsPrevention of secondary complications is similar to that for other types of AML. Supportive care includes blood products such as red blood cell and platelet transfusions as needed and treatment of infections with antibiotics. Prophylactic antibiotics and antifungal agents are administered during periods of severe neutropenia including the consolidation and post-transplantation periods [National Comprehensive Cancer Network 2009].SurveillanceSurveillance for familial AML with mutated CEBPA is similar to that for other forms of AML. There are no generally accepted minimal residual disease markers in AML with mutated CEBPA or in most other AML subtypes, including those with normal karyotypes. Patients with familial AML with mutated CEBPA who are cured of their initial disease may have an increased lifelong risk of leukemia [Pabst et al 2009]; therefore, additional surveillance, possibly lifelong, may be warranted. Patients are monitored and evaluated in accordance with administered treatment, clinical course, symptoms, and protocol, if enrolled in clinical trials. When complete remission is achieved and intensification therapy is complete, patients are monitored with:CBC and platelet counts every one to three months for two years with the frequency decreasing to every three to six months for up to five years;Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present. Note: The use of flow cytometry for minimal residual disease monitoring is controversial.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Familial Acute Myeloid Leukemia (AML) with Mutated CEBPA: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDCEBPA19q13.11CCAAT/enhancer-binding protein alphaCEBPAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Familial Acute Myeloid Leukemia (AML) with Mutated CEBPA (View All in OMIM) View in own window 116897CCAAT/ENHANCER-BINDING PROTEIN, ALPHA; CEBPA 601626LEUKEMIA, ACUTE MYELOID; AMLCEBPA encodes the CCAAT/enhancer-binding protein alpha (CEBPA), a transcription factor that plays a key role in granulocyte development. A detailed review of the role of CEBPA in human cancer has recently been published [Koschmieder et al 2009]. The role of mutation of CEBPA in the formation of AML is not well understood, and is a source of ongoing research [Pabst & Mueller 2007, Pabst & Mueller 2009].Normal germline allelic variants. CEBPA is a single-exon gene; the primary CEBPA transcript (NM_004364.3) is 2591 bp. There are two in-frame AUG start codons (codon 1 and codon 120) that result in two CEBPA protein isoforms. A few normal allelic variants in the CEBPA coding region have been reported (see Table 2). Pathologic germline allelic variants. The germline mutations identified to date are listed in Table 2; the c.217_218insC variant has been reported in two pedigrees. Thus far, reported germline mutations have been small insertions/deletions that result in frameshifts in CEBPA regions that encode the N-terminal region of the protein and predict premature termination of synthesis of the full-length CEBPA protein (see Normal gene product). Table 2. Selected CEBPA Germline Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid ChangeReference SequencesNormalc.754G>Tp.Ala252SerNM_004364.3 NP_004355.2c.713C>Ap.Ala238Gluc.690G>Tp.Thr230ThrPathologicc.68delCp.Pro23Argfs*137c.68dupCp.His24Alafs*84c.141delCp.Ala48Profs*112c.198_201dupCTACp.Ile68Leufs*41c.318_319dupTp.Asp107Valfs*54c.217_218insC 2(217insC)p.Phe73Serfs*35See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Reported in two pedigreesNormal gene product. The primary CEBPA transcript (NM_004364.3) encodes the CCAAT/enhancer binding protein alpha (C/EBP alpha), which is a transcription factor of a 358-amino-acid, 42-kd protein (reference sequence NP_004355). The full-length 42-kd protein contains two distinct N-terminal transactivation domains (mediate contact with transcriptional apparatus), a C-terminal basic region (DNA-binding), and a leucine zipper for dimerization. An alternative shorter transcript occurs when AUG codon 120 is used as an alternative start site. This shorter transcript encodes a 30-kd protein isoform that lacks the first transactivation domain and impairs interaction with the transcriptional apparatus. The C-terminal domains are intact [Pabst & Mueller 2007, Pabst & Mueller 2009]. Evidence from cell culture identified CEBPA protein as a tumor suppressor and an inhibitor of cell proliferation. Evidence from mouse models is consistent with the tumor suppressor activity being in the 42-kd isoform and transformation in the absence of 42 kd is mediated by a 30-kd isoform which has a dominant-negative effect leading to the formation of progenitors prone to deregulated proliferation and transformation [abstracted from Pabst & Mueller 2009]. Abnormal gene product. The reported germline pathologic mutations in CEBPA (Table 2) occur before codon 120 and cause/predict premature termination of synthesis of the full-length CEBPA protein, with preservation of the 30-kd isoform. The 30-kd protein is believed to inhibit the action of the normal 42-kd protein encoded by the remaining normal allele in a dominant-negative manner. Note about somatic mutations in familial AML with CEBPA mutations. The leukemic cells of most individuals with familial AML with mutated CEBPA are compound heterozygous. In addition to the germline mutation described above in the N-terminal region (see Pathologic germline allelic variants), the leukemic cells commonly acquire somatic C-terminal in frame mutation(s). C-terminal in-frame mutations disrupt the basic region and leucine zipper, impairing DNA binding as well as homo- and heterodimerization with other CEBP proteins and/or DNA binding [Pabst & Mueller 2007, Pabst & Mueller 2009]. The leukemic cells of persons with sporadic AML with CEBPA mutations have similar N-terminal and C-terminal mutations. In 50%-75% of all persons with AML with mutated CEBPA, biallelic CEBPA mutations are identified.